The purpose of this project is to identify the determinants of non-insulin-dependent diabetes (NIDDM), various types of arthritis, and gallbladder disease, and elucidate the natural history of the diseases. Genetic and environmental risk factors for NIDDM have been studied in the Pima Indians. The residents of the study area, approximately 5000 people, have participated in a longitudinal population study for the last 25 years, allowing observations of the natural history of diabetes mellitus. Risk factors for obesity, hypertension, and cholelithiasis are also studied, along with the relationships of these diseases to diabetes and their effects on mortality rates. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin, concentrations, impaired glucose tolerance, occupational and leisure-time physical activity and diabetes in relatives are assessed. The severity of abnormality of i glucose homeostasis is assessed by measurement of plasma glucose and serum insulin concentrations during glucose tolerance tests and measurement of glycosylated hemoglobin. This study has shown diabetes to be a serious and common disease with both genetic and environmental components. Hyperinsulinemia, reflecting insulin resistance, is an early abnormality predicting diabetes. The deterioration from impaired glucose tolerance to diabetes may be precipitated by insulin secretory failure.